Tuberculosis (TB), caused by Mycobacterium tuberculosis (Mtb) is the number one cause of deaths due to a single infectious agent worldwide. The treatment of TB is lengthy and often complicated by the increasing drug resistance. New compounds with new mechanisms of action are therefore needed. We present the design, synthesis, and biological evaluation of pyrazine-based inhibitors of a prominent antimycobacterial drug target - mycobacterial methionine aminopeptidase 1 (MtMetAP1). The inhibitory activities of the presented compounds were evaluated against the MtMetAP1a isoform, and all derivatives were tested against a broad spectrum of myco(bacteria) and fungi. The cytotoxicity of the compounds was also investigated using Hep G2 cell lines. Overall, high inhibition of the isolated enzyme was observed for 3-substituted N-(thiazol-2-yl)pyrazine-2-carboxamides, particularly when the substituent was represented by 2-substituted benzamide. The extent of inhibition was strongly dependent on the used metal cofactor. The highest inhibition was seen in the presence of Ni2+. Several compounds also showed mediocre in vitro potency against Mtb (both Mtb H37Ra and H37Rv). Despite the structural similarities of bacterial and fungal MetAP1 to mycobacterial MtMetAP1, title compounds did not exert antibacterial nor antifungal activity. The reasons behind the higher activity of 2-substituted benzamido derivatives, as well as the correlation of enzyme inhibition with the in vitro growth inhibition activity is discussed.

• MeSH
• aminopeptidasy antagonisté a inhibitory   metabolismus   MeSH
• antituberkulotika MeSH
• inhibitory enzymů chemická syntéza   chemie   farmakologie   MeSH
• mikrobiální testy citlivosti MeSH
• molekulární struktura MeSH
• Mycobacterium tuberculosis účinky léků   enzymologie   MeSH
• pyraziny chemická syntéza   chemie   farmakologie   MeSH
• racionální návrh léčiv * MeSH
• vztah mezi dávkou a účinkem léčiva MeSH
• vztahy mezi strukturou a aktivitou MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH

The complexity of Alzheimer's disease (AD) calls for search of multifunctional compounds as potential candidates for effective therapy. A series of phthalimide and saccharin derivatives linked by different alicyclic fragments (piperazine, hexahydropyrimidine, 3-aminopyrrolidine or 3-aminopiperidine) with phenylalkyl moieties attached have been designed, synthesized, and evaluated as multifunctional anti-AD agents with cholinesterase, β-secretase and β-amyloid inhibitory activities. In vitro studies showed that the majority of saccharin derivatives with piperazine moiety and one phthalimide derivative with 3-aminopiperidine fragment exhibited inhibitory potency toward acetylcholinesterase (AChE) with EeAChE IC50 values ranging from 0.83 μM to 19.18 μM. The target compounds displayed inhibition of human β-secretase-1 (hBACE1) ranging from 26.71% to 61.42% at 50 μM concentration. Among these compounds, two multifunctional agents (26, [2-(2-(4-benzylpiperazin-1-yl)ethyl)benzo[d]isothiazol-3(2H)-one 1,1-dioxide] and 52, 2-(2-(3-(3,5-difluorobenzylamino)piperidin-1-yl)ethyl)isoindoline-1,3-dione) have been identified. Compound 26 exhibited the highest inhibitory potency against EeAChE (IC50 = 0.83 μM) and inhibitory activity against hBACE1 (33.61% at 50 μM). Compound 52 is a selective AChE inhibitor (IC50 AChE = 6.47 μM) with BACE1 inhibitory activity (26.3% at 50 μM) and it displays the most significant Aβ anti-aggregating properties among all the obtained compounds (39% at 10 μM). Kinetic and molecular modeling studies indicate that 26 may act as non-competitive AChE inhibitor able to interact with both catalytic and peripheral active site of the enzyme.

• MeSH
• aminy chemie   farmakologie   MeSH
• amyloidní beta-protein metabolismus   MeSH
• cholinesterasy metabolismus   MeSH
• ftalimidy chemická syntéza   chemie   farmakologie   MeSH
• hematoencefalická bariéra účinky léků   MeSH
• inhibiční koncentrace 50 MeSH
• inhibitory enzymů chemická syntéza   chemie   farmakologie   MeSH
• lékové transportní systémy MeSH
• lidé MeSH
• molekulární struktura MeSH
• patologická konformace proteinů MeSH
• peptidové fragmenty metabolismus   MeSH
• racionální návrh léčiv MeSH
• sacharin chemická syntéza   chemie   farmakologie   MeSH
• sekretasy metabolismus   MeSH
• vazba proteinů účinky léků   MeSH
• vazebná místa MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH

The multitarget approach is a promising paradigm in drug discovery, potentially leading to new treatment options for complex disorders, such as Alzheimer's disease. Herein, we present the discovery of a unique series of 1-benzylamino-2-hydroxyalkyl derivatives combining inhibitory activity against butyrylcholinesterase, β-secretase, β-amyloid, and tau protein aggregation, all related to mechanisms which underpin Alzheimer's disease. Notably, diphenylpropylamine derivative 10 showed balanced activity against both disease-modifying targets, inhibition of β-secretase (IC50  hBACE-1 = 41.60 μM), inhibition of amyloid β aggregation (IC50 Aβ = 3.09 μM), inhibition of tau aggregation (55% at 10 μM); as well as against symptomatic targets, butyrylcholinesterase inhibition (IC50  hBuChE = 7.22 μM). It might represent an encouraging starting point for development of multifunctional disease-modifying anti-Alzheimer's agents.

• MeSH
• Alzheimerova nemoc farmakoterapie   metabolismus   MeSH
• amyloidní beta-protein účinky léků   metabolismus   MeSH
• butyrylcholinesterasa farmakologie   MeSH
• cholinesterasové inhibitory farmakologie   MeSH
• lidé MeSH
• peptidové fragmenty metabolismus   MeSH
• proteiny tau účinky léků   MeSH
• racionální návrh léčiv * MeSH
• simulace molekulového dockingu metody   MeSH
• vztahy mezi strukturou a aktivitou MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH

We report herein the straightforward two-step synthesis and biological assessment of novel racemic benzochromenopyrimidinones as non-hepatotoxic, acetylcholinesterase inhibitors with antioxidative properties. Among them, compound 3Bb displayed a mixed-type inhibition of human acetylcholinesterase (IC50 = 1.28 ± 0.03 μM), good antioxidant activity, and also proved to be non-hepatotoxic on human HepG2 cell line.

• MeSH
• Alzheimerova nemoc prevence a kontrola   MeSH
• antioxidancia chemická syntéza   farmakologie   MeSH
• cholinesterasové inhibitory chemická syntéza   farmakologie   MeSH
• inhibiční koncentrace 50 MeSH
• játra účinky léků   MeSH
• lidé MeSH
• spektrální analýza MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH

Alzheimer's disease (AD) is a major public health problem, which is due to its increasing prevalence and lack of effective therapy or diagnostics. The complexity of the AD pathomechanism requires complex treatment, e.g. multifunctional ligands targeting both the causes and symptoms of the disease. Here, we present new multitarget-directed ligands combining pharmacophore fragments that provide a blockade of serotonin 5-HT6 receptors, acetyl/butyrylcholinesterase inhibition, and amyloid β antiaggregation activity. Compound 12 has displayed balanced activity as an antagonist of 5-HT6 receptors ( Ki = 18 nM) and noncompetitive inhibitor of cholinesterases (IC50 hAChE = 14 nM, IC50 eqBuChE = 22 nM). In further in vitro studies, compound 12 has shown amyloid β antiaggregation activity (IC50 = 1.27 μM) and ability to permeate through the blood-brain barrier. The presented findings may provide an excellent starting point for further studies and facilitate efforts to develop new effective anti-AD therapy.

• MeSH
• Alzheimerova nemoc farmakoterapie   etiologie   MeSH
• amyloidní beta-protein metabolismus   MeSH
• butyrylcholinesterasa farmakologie   MeSH
• cholinesterasové inhibitory farmakologie   MeSH
• lidé MeSH
• ligandy * MeSH
• molekulární modely MeSH
• peptidové fragmenty metabolismus   MeSH
• racionální návrh léčiv MeSH
• simulace molekulového dockingu MeSH
• vztahy mezi strukturou a aktivitou MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH

Looking for an effective anti-Alzheimer's agent is very challenging; however, a multifunctional ligand strategy may be a promising solution for the treatment of this complex disease. We herein present the design, synthesis and biological evaluation of novel hydroxyethylamine derivatives displaying unique, multiple properties that have not been previously reported. The original mechanism of action combines inhibitory activity against disease-modifying targets: β-secretase enzyme (BACE1) and amyloid β (Aβ) aggregation, along with an effect on targets associated with symptom relief - inhibition of butyrylcholinesterase (BuChE) and γ-aminobutyric acid transporters (GATs). Among the obtained molecules, compound 36 exhibited the most balanced and broad activity profile (eeAChE IC50 = 2.86 μM; eqBuChE IC50 = 60 nM; hBuChE IC50 = 20 nM; hBACE1 IC50 = 5.9 μM; inhibition of Aβ aggregation = 57.9% at 10 μM; mGAT1 IC50 = 10.96 μM; and mGAT2 IC50 = 19.05 μM). Moreover, we also identified 31 as the most potent mGAT4 and hGAT3 inhibitor (IC50 = 5.01 μM and IC50 = 2.95 μM, respectively), with high selectivity over other subtypes. Compounds 36 and 31 represent new anti-Alzheimer agents that can ameliorate cognitive decline and modify the progress of disease.

• MeSH
• Alzheimerova nemoc farmakoterapie   metabolismus   MeSH
• butyrylcholinesterasa metabolismus   MeSH
• cholinesterasové inhibitory chemická syntéza   chemie   farmakologie   MeSH
• lidé MeSH
• molekulární struktura MeSH
• neuroprotektivní látky chemická syntéza   chemie   farmakologie   MeSH
• objevování léků * MeSH
• proteiny přenášející GABA přes plazmatickou membránu metabolismus   MeSH
• vztah mezi dávkou a účinkem léčiva MeSH
• vztahy mezi strukturou a aktivitou MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH